Changes in LTP/LTD at 26

Cognitive Impairment at 17

Cognitive impairment manifests at 4 months as a deficit in long-term retention and correlates with the accumulation of intraneuronal Aβ in the hippocampus and amygdala, but plaques and tangles are not yet apparent (Billings et al., 2005).

Age-related, progressive neuropathology including plaques and tangles. Extracellular Aβ deposits by 6 months in frontal cortex, more extensive by 12 months. No tau pathology at 6 months, but evident at 12 months. Synaptic dysfunction, including LTP deficits, prior to plaques and tangles.

Cognitive impairment by 4 months. Impairments first manifest as a retention/retrieval deficit and not as a learning deficit, and occur prior to plaques and tangles. Deficits in both spatial and contextual based paradigms. Clearance of intraneuronal Aβ by immunotherapy rescues the early cognitive deficits in a hippocampal-dependent task.

Observed

X

Neuronal Loss at 39

Neuron loss in cortical layer 5 and subiculum.

X

Plaques at 7

Amyloid deposition begins at 1.5 months and reaches high levels especially in subiculum and deep cortical layers. Aβ42 also accumulates intraneuronally in an aggregated form within the soma and neurites starting at 1.5 months (Oakley et al., 2006).

X

Gliosis at 9

Gliosis begins at 2 months (Oakley et al., 2006).

X

Synaptic Loss at 39

Synaptic markers synaptophysin, syntaxin, and PSD-95 decrease with age and are significantly reduced by 9 and 12 months.

X

Changes in LTP/LTD at 26

LTP is normal in young animals, but becomes impaired around 6 months (Kimura et al., 2009); specifically, in hippocampal slices from < 4-month-old mice, I/O curves of fEPSPs were not different from those of wild-type controls, but the I/O responses at Schaffer collateral-CA1 synapses at 6 months were impaired.

Observed

X

Plaques at 9

Vascular amyloid deposits and punctate parenchymal aggregates first occur in the hippocampus and increase with age, spreading throughout the brain, including the cortex, amygdala, thalamus, and brainstem in hemizygous mice.

X

Gliosis at 17

Astrogliosis and microgliosis increase with age and increasing ADan-amyloid deposition.

X

Cognitive Impairment at 78

The only ages tested were 6 months and 18-20 months. Mice 18-20 months of age exhibited both motor and spatial learning defects in the Morris water maze, and increased anxiety in the open field test. No impairments were observed in 6 month-old mice.

ADan deposition starts in the hippocampus and meningeal vessels at 2 months and increases with age. By 18 months, deposition is widespread. The majority of amyloid deposits are associated with the vasculature, where they destroy the integrity of the vessel wall and lead to microhemorrhages. Parenchymal amyloid plaques surrounded by microglia and dystrophic neurites are also present.

Impaired performance in Morris water maze, due to a combination of both motor deficits (i.e. reduced swim speed) and spatial learning deficits reported at 18-20 months. Open field test at 18-20 months also showed an anxiety-related phenotype.

Observed

Absent

No Data

Observed

X

Neuronal Loss at 61

Neuronal loss (14-28%) has been reported in the CA1 region of the hippocampus in 14-18 month old mice (Calhoun et al., 1998).

X

Plaques at 26

Congophillic, dense-core amyloid plaques first appear at 6 months, and increase in size and number with age. Amyloid plaques can occupy more than 25% of the neocortex and hippocampus in 24 month-old mice (Sturchler-Pierrat et al., 1997; Calhoun et al., 1998).

No Data

Aβ deposits first observed at 6 months. Congophilic plaques increase in size and number with age and are surrounded by activated microglia, astrocytes, and dystrophic neurites containing hyperphosphorylated tau (although no neurofibrillary tangles). Neuronal loss in the CA1 region of the hippocampus. Mice also develop CAA, and microhemorrages occur at later ages.

Spatial memory defects in Morris Water maze at 3 months and progresses with age. Memory deficits in passive avoidance were observed in 25 month-old mice, but not at younger ages.

Neuronal Loss at

Synaptic Loss at

Changes in LTP/LTD at

Amyloid deposition by 6 months of age in the cortex and hippocampus. Abundant reactive astrocytes in the vicinity of plaques. Elevated Aβ43 in the brain by 3 months. High density of cored plaques. Pyroglutamate Aβ (N3pE-Aβ) associated with amyloid plaques.

Short-term memory deficits apparent by 3-4 months as measured by the Y maze.

Synaptic Loss at 24

Changes in LTP/LTD at 28

At 6 months there is a large reduction of long-term potentiation and disrupted paired pulse facilitation. No deficit at 4 months (Breyhan et al., 2009).

X

Cognitive Impairment at 27

Age-dependent impairments in working memory as measured by the Y maze and T-maze continuous alternation task. No deficit at 2 months, but deficits at 6 and 12 months compared to PS1KI littermates (Wirths et al., 2008).

Absent

Tangles at

Absent.

No Data

Acceleration of extracellular Aβ deposition compared to the single transgenics. Age-dependent neuronal loss in the hippocampus with extensive neuronal loss in the CA1/2 at 10 months with detection as early as 6 months in female mice. Intraneuronal Aβ and thioflavin-S-positive deposits before neuronal loss. Astrogliosis in proximity of Aβ-positive neurons.

Age-dependent impairments in working memory as measured by the Y maze and T-maze continuous alternation task. No deficit at 2 months, but deficits at 6 and 12 months compared to PS1KI littermates.

Observed

Absent

No Data

Genes

Mutations

Modification

Disease

Neuropathology

Behavior/Cognition

APP

APP: Transgenic

Alzheimer's Disease

No neuropathology up to age 29 months; however, pathology reminiscent of inclusion body myopathy observed at 6-12 months: Aβ-immunoreactive deposits in skeletal muscle fibers. Muscle fibers with Aβ-immunoreactive deposits increased with age and also became vacuolated.

Hypoactivity. The acquisition of place learning in the Morris water maze task was impaired.

Observed

X

Gliosis at 126

Microgliosis develops after the onset of CAA pathology and is prominent in areas adjacent to amyloid-laden vessels. There is also widespread activation of astrocytes in neocortical regions affected by CAA. These changes have been reported at 29 months of age, although the actual onset of gliosis may occur earlier than has been examined.

Observed

Neuronal Loss at 104

Neuronal loss, as measured by NeuN staining, was observed in the CA3 region of the hippocampus at 24 months of age. Neuronal loss was not detected in the cerebral cortex at this time.

X

Gliosis at 52

At 12 months of age, microgliosis is seen in transgenic mice, as measured by the presence of Iba-1 staining in the hippocampus and cortex. Astrocytosis, as measured by GFAP-reactivity, increased starting around 18 months of age in these regions.

X

Synaptic Loss at 34

Starting around eight months of age, transgenic mice exhibit a decrease in synaptic density in the CA3 region of the hippocampus as measured by synaptophysin staining.

X

Changes in LTP/LTD at 35

By eight months of age, transgenic mice exhibit reduced short term plasticity as measured by paired-pulse facilitation in addition to reduced LTP as elicited by high frequency stimulation to the perforant pathway.

No Data

Age-dependent accumulation of Aβ oligomers within hippocampal and cortical neurons, but negligible deposits of extracellular amyloid. Abnormal tau phosphorylation, but no overt tangle pathology. Synaptic loss and gliosis in hippocampus and cerebral cortex. Late neuronal loss in the CA3 region of the hippocampus.

Memory impairment by eight months as measured by the Morris water maze. Specifically, reduced spatial reference memory in the Morris water maze compared to mice expressing comparable levels of wild-type human APP.

Synaptic Loss at 39

Cognitive Impairment at 78

Memory impairment in homozygous mice at 18 months as measured by the Y maze test. APPNL/NL mice (with Swedish mutation only) were unimpaired at this age. No significant deficit was seen in the Morris water maze at 18 months.

Absent

Neuronal Loss at

Absent.

Tangles at

Absent; although elevated levels of phosphorylated tau are observed in dystrophic neurites around plaques.

Observed

X

Neuronal Loss at 74

Global neuron loss is not observed, but modest neuron loss was found in the granule cell layer of the dentate gyrus and other subregions with high neuronal density in 17-month old animals (Rupp et al., 2011).

X

Plaques at 6

Aβ deposition begins at 6 weeks of age in the cortex and 3-4 months of age in the hippocampus (Radde et al., 2006).

X

Gliosis at 6

Activated microglia around Aβ deposits at 6 weeks as well as increased astrogliosis (Radde et al., 2006). Levels of CCL2 and TNFα increase at later ages (Lee et al., 2010).

X

Synaptic Loss at 10

Dendritic spine loss around plaques reported to begin approximately 4 weeks after plaque formation and continue for several months (Bittner et al., 2012).

X

Changes in LTP/LTD at 35

Hippocampal CA1 LTP normal at 4.5 months of age, but impaired at 8 and 15 months of age (Gengler et al., 2010).

No Data

Amyloid plaque deposition starts at approximately 6 weeks in the neocortex. Amyloid deposits in the hippocampus appear at 3-4 months, and in the striatum, thalamus and brainstem at 4-5 months. Phosphorylated tau-positive neuritic processes have been observed in the vicinity of all congophilic amyloid deposits, but no fibrillar tau inclusions are seen.

Cognitive deficits in spatial learning and memory in the Morris water maze reported at 7 months. Impaired reversal learning of a food-rewarded four-arm spatial maze task at 8 months.

Observed

X

Neuronal Loss at 39

Progressive neuronal degeneration including reduced neurite density and reduced neuronal number in the cortex and hippocampus of APPsw/0; Pdgfrβ+/- mice at at nine monthscompared to age-matched APPsw/0; Pdgfrβ+/+ littermates.

X

Plaques at 39

By 9 months of age APPsw/0;Pdgfrβ+/- mice have an elevated plaque load in the cortex and hippocampus compared with age matched APPsw/0;Pdgfrβ+/+. littermates. They also have extensive cerebral amyloid angiopathy.

Absent

No Data

Tangles at

Although mature neurofibrillary tangles were not observed by 9 months (the oldest age assessed), the mice develop significant tau pathology, including tau hyperphosphorylation in cortical and hippocampal neurons. Pre-tangle pathology is observed, including neuronal caspase-cleaved tau, and conformational changes as indicated by the conformation-specific antibody MC1.

Changes in LTP/LTD at

Plaques especially in the thalamus and subiculum. Aggregated, hyperphosphorylated tau tangles. Neuronal loss especially of NPY neurons in the hippocampus and subiculum. More severe pathology than Tg-SwDI alone.

Severe learning and memory deficits. Impaired spatial memory compared to Tg-SwDI as measured by the radial arm maze and the Barnes maze at 52-56 weeks.

Observed

Absent

No Data

Amyloid plaques by 17-18 months in the neocortex and hippocampus with detection of 5-10 fold more Aβ40 than Aβ42. Plaque burden significantly lower than in the double transgenic PS2APP. Lower levels of insoluble Aβ40 and Aβ42 than the PS2APP mouse at 16-18 months.

Neuronal Loss at

Synaptic Loss at

Cognitive Impairment at

By 14-16 months, homozygotes have diffuse and compact Aβ deposits in the frontal cortex, by 18-20 months plaques throughout the cortex and olfactory bulb with occasional deposits in the corpus callosum and hippocampus. No tangles, but some changes in phosphorylated tau. Reactive astrocytes and microglia by 14-16 months.

Observed

X

Plaques at 39

By 9 months of age, amyloid plaques develop in the hippocampus and subiculum, later extending to the cortex (Borchelt et al., 1997). The striatum and thalamus are relatively spared out to 18 months of age. Amyloid pathology is more severe in female mice, with a greater amyloid burden measured at 12 and 17 months of age (Wang et al., 2003).

X

Gliosis at 52

By one year of age, reactive gliosis is observed in the cortex and hippocampus and is associated with dystrophic neurites (Borchelt et al., 1997).

X

Cognitive Impairment at 48

Age-associated cognitive impairment, as measured by the Morris water maze, was observed in 11 to 12-month-old males. Both acquisition and retention were impaired. No impairment at 3-4 months of age. At both time points mice performed normally on a position discrimination task in the T-maze (Puoliväli et al., 2002).

Absent

Neuronal Loss at

There was no difference in neuronal numbers in the cingulate cortex compared with wild-type mice (Xiang et al., 2002).

Tangles at

Not observed.

No Data

Synaptic Loss at

No data.

Changes in LTP/LTD at

Amyloid plaques by 9 months, starting in the hippocampus and subiculum. Plaques later develop in the cortex; the striatum and thalamus are relatively spared. Amyloid pathology is more severe in females. Dystrophic neurites and gliosis in the cortex and hippocampus.

Poor nest building. Reduced retention in a learned passive avoidance task. Increased immobility time in forced swim task. Age-associated impairment in acquisition and retention in the Morris water maze. No impairment in a position discrimination T-maze task.

Synaptic Loss at 17

Changes in LTP/LTD at 13

Transient long-term potentiation (t-LTP) is reduced by 3 months. The degree of impairment is not related to age from 3 to 12 months (Volianskis et al., 2008).

X

Cognitive Impairment at 52

Impairment in the Morris water maze at 12 months, specifically during acquisition of the hidden platform sub-task and the probe trial, but not in the visible platform test (Lalonde et al., 2005). At 13 months the mice commit more errors in the Morris water maze, but not at 7 months (Volianskis et al., 2008).

Absent

Tangles at

Not observed.

No Data

Occasional Aβ deposits by 6 months with abundant plaques in the hippocampus and cortex by 9 months and a progressive increase in plaques up to 12 months. No tangles. Decrease in synaptic markers and increase in complement immunoreactivity.

Observed

X

Cognitive Impairment at 117

Impairments at the water finding task at age 27-29 months, a test of long-term memory. No differences in the open field test of the elevated plus maze indicating no difference in general behavioral patterns, activity level, or emotional state.

At 27-29 months mice displayed long-term memory deterioration. Acquisition of spatial memory is slightly affected, but no deterioration in short-term working memory. No difference in open field test or elevated plus maze suggesting no difference in overall behavioral patterns or activity levels.

From the age of 6 months, spatial and non-spatial orientation and memory deficits by Morris water maze. Impaired associative learning. Increased agitation/anxiety from 8 weeks. Reduced ambulation, especially with age. Hyperactivity and aggression.

Gliosis at 13

Cognitive Impairment at 13

At 3-4 months the Arc48 mouse was able to learn a task involving escape to a cued platform in the Morris water maze, but were impaired in the ability to use extramaze cues to navigate to the hidden platform (Cheng et al., 2007).

At 3-4 months the Arc48 mouse was able to learn a task involving escape to a cued platform in the Morris water maze, but had an impaired ability to use extramaze cues to navigate to the hidden platform.

Observed

X

Plaques at 39

Between 9 and 15 months of age β-amyloid plaques became prominent. Plaques had a characteristic dense core morphology which differed from the cotton wool-like structure of plaques seen with the Swedish mutation alone (Knobloch et al., 2007).

X

Changes in LTP/LTD at 15

LTP is severely impaired in slices from 3.5 and 7.5 month old mice. LTP and basal synaptic transmission were normal in slices from one month old mice (Knobloch et al., 2007).

X

Cognitive Impairment at 26

Cognitive impairment measured from the age of 6 months in the Morris water maze and Y-maze, as well as in active avoidance behavior (Knobloch et al., 2007).

Absent

Tangles at

Absent.

No Data

Synaptic Loss at

At 6 months intracellular punctate deposits of Aβ abundant in cortex and hippocampus, but overt β-amyloid plaques not apparent until 9-15 months. Severe CAA also present at this age with dense Aβ aggregates in blood vessels walls and spreading into the parenchyma.

Cognitive impairments from the age of 6 months measured in the Morris water maze and Y-maze.

Observed

X

Plaques at 13

Robust and reliable plaque pathology as early as 3 months in homozygotes, 5 months in hemizygotes. Plaques start in the anterior neocortex and subiculum, spreading to other brain regions (e.g. hippocampus, thalamus, amygdala). Congophilic dense-core plaques are abundant, with lower levels of diffuse plaques and some cerebral amyloid angiopathy.

X

Gliosis at 22

Glial activation, including reactive astrocytes and activated microglia, is present in areas around plaques by 5 months of age in homozygous animals, later in hemizygotes.

X

Synaptic Loss at 13

Decreased expression of synaptophysin mRNA in the brain by 3-4 months of age in both hemizygous and homozygous animals.

Cognitive Impairment at 52

Absent

Neuronal Loss at

Outright neuronal loss has not been documented, but substantial degeneration of dendritic arbors occurs by 10-14 months of age in hippocampal neurons.

Tangles at

No tangles or neuropil threads, but some hyperphosphorylated tau by eight months in dystrophic neurites.

No Data

Changes in LTP/LTD at

Unknown; however, hippocampal neurons exhibit substantial changes in electrophysiological properties by 10-14 months of age, including hyperexcitability in the form of increased firing of action potentials and a more efficient transition from solitary firing to bursting.

Observed

X

Plaques at 13

Detergent-insoluble amyloid-β and cored plaques as early as three months in the cerebellum. Variable forebrain pathology later with extracellular Aβ plaques in the hippocampus and entorhinal/piriform cortices by 12 months. Extensive congophillic amyloid angiopathy.

Tangles at

Cognitive Impairment at

No Data

Genes

Mutations

Modification

Disease

Neuropathology

Behavior/Cognition

Transgenic

Alzheimer's Disease, Cerebral Amyloid Angiopathy

Detergent-insoluble amyloid-β appearing with age and cored plaques as early as 3 months in the cerebellum. Variable forebrain pathology later with extracellular Aβ plaques in the hippocampus and entorhinal/piriform cortices at 12 months. Age-associated congophillic amyloid angiopathy. No tangles or neuronal loss.

Observed

Absent

No Data

Observed

X

Neuronal Loss at 43

Decrease in cortical thickness and reduced cell number between 10 and 14 months of age. Increased ventricle size increased from age eight months to 18 months. Decrease in the thickness of the corpus callosum (Andorfer et al., 2005).

X

Tangles at 39

Aggregated tau and paired helical filaments detectable at nine months by immunoelectron microscopy, although paired helical filaments of aggregated insoluble tau can be isolated from brain tissue as early as two months. Tau first redistributes from axons to cell bodies. Hyperphosphorylated tau begins to accumulate by six months, and increases further by 13 and 15 months (Andorfer et al., 2003).

X

Changes in LTP/LTD at 52

In hippocampal slices, LTP induced by high frequency stimulation (HFS) was normal at four months but abolished by 12 months. LTP induced by theta burst stimulation (TBS) was normal at both ages. Paired-pulse ratio (PPR) was unaffected at four months, but increased at 12 months compared with controls, suggesting a decrease in probability of transmitter release (Polydoro et al., 2009).

Observed

X

Neuronal Loss at 87

Neuron loss in the hippocampus was observed by 20 months.

X

Gliosis at 17

Astrocytosis, but no differences in microglia.

X

Cognitive Impairment at 74

In the Morris water maze, performance was impaired after 17 months of age. Nest building was impaired at 10-14 months. Social interaction, anxiety, exploratory behavior, and motor functions were unaltered.

Absent

Tangles at

Abnormal accumulations of soluble tau were observed, but not tangles or tangle-like structures.

Tangles at 13

Gliosis at 43

Astrocytosis and microgliosis at 10 months.

X

Synaptic Loss at 87

Synaptophysin, but not PSD95, decreased in hippocampus and cortex at 12 months. By Golgi staining, spines unchanged in CA1 at 10 months, increased in CA3 at 12 months, and decreased in CA1 and CA3 at 16 months.

X

Cognitive Impairment at 70

No change at 10 months but at 16 months deficits in learning and memory (Morris water maze).

Synaptic Loss at

Changes in LTP/LTD at

Age-dependent hyperphosphorylation of tau and conformational changes leading to neurofibrillary tanglelike pathology in the cerebral cortex, hippocampus, brain stem, and spinal cord. Neurodegeneration, especially in the spinal cord, accompanied by astrocytosis.

Early motor impairment, including abnormal clasping and rotarod deficit at 4 months, with nearly complete deficit at 5 months. Deficits progress to severe paraparesis. Disinhibition and hyperactivity at 2 to 3 months.

Observed

Absent

No Data

Observed

X

Neuronal Loss at 12

Cell loss varies by brain region. No significant neuronal loss was observed in the CA3 region of the hippocampus at 6, 12, 24 and 36 weeks of age nor in the CA1 region at 6 weeks; however, at 12, 24, and 36 weeks significant neuronal loss was observed in the CA1 region compared to age-matched wild-type animals (Wright et al., 2013).

X

Plaques at 22

At 5-7 months of age diffuse amyloid-β plaques deposit in the dentate gyrus and neocortex. Amyloid deposition is progressive with widespread plaques by 8-10 months. Aβ puncta are deposited in the hippocampus as early as 1 month (Hong et al., 2016).

X

Gliosis at 24

At 24 and 36 weeks a significant increase in the number of reactive GFAP+ astrocytes and CD68+ microglia was observed in the hippocampi of J20 mice compared to age-matched wild-type controls. No significant difference was observed at 6 and 12 weeks (Wright et al., 2013).

X

Synaptic Loss at 15

Age-dependent loss of synaptophysin, synaptotagmin, PSD-95, and homer immunoreactivity in the hippocampus by 3 months; synapse loss was confirmed by electron microscopy. No significant difference was seen at 1 month (Hong et al., 2016).

X

Changes in LTP/LTD at 13

Basal synaptic transmission is impaired between 3-6 months; extracellularly recorded field EPSPs at the Schaffer collateral to CA1 synapse in acute hippocampal slices were on average smaller in amplitude than those seen in wild-type mice. Significant deficits in LTP at the Schaffer collateral–CA1 synapse compared with control mice at 3-6 months (Saganich et al., 2006).

X

Cognitive Impairment at 16

Deficits in spatial memory and learning appear as the mice age. As early as 16 weeks mice demonstrate spatial reference memory deficits as measured by the radial arm maze (Wright et al., 2013). By 6-7 months deficits appear in spatial memory retention and acquisition in the water maze (Palop et al., 2003).

Learning and memory deficits are age-dependent and may appear as early as 16 weeks. Hyperactivity and increased time in the open arm of the elevated plus maze than wild-type mice indicating lower levels of anxiety, but has not been universally replicated.

Cognitive Impairment at

Age and gene-dose dependent development of neurofibrillary tangles as early as 4.5 months in homozygotes and 6.5 months in heterozyotes. Tangles and Pick-body-like inclusions in the amygdala, hypothalamus, pons, medulla, and spinal cord among other areas. Neuronal loss, especially in the spinal cord.

By 10 months, 90% developed motor and behavioral disturbances including limb weakness, hunched posture, decrease in grooming and vocalization.

Observed

Neuronal Loss at 34

Neuronal loss occurred by 8-10 months as evidenced by decreased NeuN staining in the dentate gyrus and CA3 regions of the hippocampus. Neocortical volume also decreased.

X

Tangles at 34

Pick-body like inclusions of aggregated tau appeared in the hippocampus and cortex by 8-10 months. Inclusions were positive for Bielchowsky silver stain but negative for Gallyas-silver stain and Thioflavin-S.

X

Gliosis at 35

Astrogliosis was seen by 8-10 months in the neocortex and hippocampus. Some GFAP+ astrocytes also contained 3R tau.

X

Cognitive Impairment at 26

By 6-8 months memory impairment was evident as a failure to habituate to a novel environment. This deficit was not present at 3-4 months. At 8-10 months, transgenics also took longer than wild-type mice to find the hidden platform in the Morris water maze.

Changes in LTP/LTD at

Accumulation of 3R tau in neurons of the cortex and hippocampus. Pick body-like tau aggregates and neuronal loss in the hippocampus and cortex. Astrogliosis, with some 3R tau in GFAP-positive astrocytes. Synapto-dendritic changes and mitochondrial pathology.

Age-related memory and motor deficits as assessed by habituation to a novel environment, the Morris water maze, and the round beam test.

Tangles at

No Data

Changes in LTP/LTD at

Age-dependent increases in Aβ40 and Aβ42, with Aβ42 > Aβ40. Plaques at an early age, starting at 3-6 months in the frontal cortex. At 5-7 months, size and number of plaques increased in the frontal cortex, and dense amyloid deposits appear in hippocampous, thalamus, and olfactory region.

Age-associated impairment in spatial memory and learning in the water maze task and habituation in the hole-board task, with significant deficits at 6 months of age. Some gender-specific differences in open field exploration.

Observed

Plaques at 8

Aβ deposits were observed as early as two months of age. These deposits were diffuse and extracellular and had a “cotton-like” appearance. Classic mature plaques were not observed.

X

Gliosis at 95

Gliosis was noted in a single 22-month-old animal with extensive Aβ deposits (Higgins et al., 1994).

X

Cognitive Impairment at 52

Deficits in spatial memory and learning appear as the mice age. At 12 months the mice demonstrate learning and memory deficits as measured by a water-maze task and in spontaneous alternation in a Y maze (Moran et al., 1995). At six months cognition is largely normal.

Absent

Neuronal Loss at

Cell death was not formally assessed, however, overt neuronal death was not seen.

Tangles at

Classic tangles were not observed, but aberrant tau immunoreactivity was observed as early as two months.

No Data

Synaptic Loss at

Unknown.

Changes in LTP/LTD at

Unknown.

Genes

Mutations

Modification

Disease

Neuropathology

Behavior/Cognition

APP

APP: Transgenic

Alzheimer's Disease

Age-dependent increase in Aβ deposits and tau immunoreactivity.

Learning and memory deficits are age-dependent as assessed on spontaneous alternation in a Y maze and in the water-maze task.

Observed

X

Plaques at 26

In heterozygous mice no plaque pathology at 4-6 months. At 6-9 months mice begin to exhibit deposits of human Aβ in the hippocampus, corpus callosum, and cerebral cortex. Plaques become more extensive with age and vary in size and structure including diffuse irregular plaques and compact cored plaques (Games et al., 1995).

Synaptic Loss at 35

Changes in LTP/LTD at 17

Alterations in LTP induced by theta burst stimulation at 4-5 months which is prior to plaque formation; although the potentiation immediately after TBS was comparable to control mice, the potentiation decayed more rapidly in PDAPP mice. Also paired pulse facilitation was enhanced. Responses to high frequency stimulation bursts were distorted (Larson et al., 1999).

Observed

Absent

No Data

Amyloid plaques at 8-10 months, but not at 2-4 months when deficits in synaptic transmission are observed. Approximately 20% of mice had plaques at 5-7 months, 50% at 8-10 months, and 100% by 21-25 months.

Observed

Gliosis at 52

Changes in LTP/LTD at 26

Impairments in long-term and short-term hippocampal plasticity. LTP following theta-burst stimulation decayed faster and paired-pulse facilitation was reduced relative to wild-type mice at both six and 12 months of age. Synaptic transmission impacted at 12 months.

X

Cognitive Impairment at 22

Social recognition memory was impaired by five months and further impaired by 12 months. Similarly, object recognition memory was impaired by eight months. Spatial learning impairments were seen later; at 12 months deficits in spatial acquisition learning were seen in the open field water maze that were not apparent at 5 months.

Absent

Neuronal Loss at

Absent.

Plaques at

Sparse plaques out to 21 months of age. Only marginally increased compared with wild-types and overall very low compared to over-expression models. However, Aβ accumulated intracellularly and also formed oligomers.

Tangles at

No overt tangle pathology; however, hyyperphosphorylated tau accumulated in the hippocampus and cortex from six months of age.

Age-related neuropathology including intraneuronal and oligomeric Aβ accumulation and hyperphosphorylated tau in the hippocampus and cortex from six months. Minimal amyloid plaques up to 21 months. Subtle tau pathology, but no overt tangles. Cortical hypometabolism with increased metabolic activity in basal forebrain and ventral midbrain by FDG-PET/CT.

Cognitive deficits in recognition memory and spatial learning emerging between five and 12 months. Impairments in hippocampal plasticity.

Observed

Gliosis at 52

Increased GFAP-positive astrocytes at 12 months of age in the dentate gyrus, CA1 region of the hippocampus, and the piriform cortex. Gliosis is suspected to begin earlier than 12 months.

X

Cognitive Impairment at 13

Impaired spatial representation in a habituation task by 3 months of age. By 6 months, impaired learning and memory by a variety of tasks including the Y-maze, Morris water maze, and a test of the social transmission of food preference. These effects appear to be distinct from reduced motor activity and reduced anxiety.

Plaques at

Tangles at

Preliminary analysis did not find abnormal phosphorylation or conformational changes in tau.

No Data

Neuronal Loss at

Unknown.

Synaptic Loss at

Unknown.

Changes in LTP/LTD at

Unknown.

Genes

Mutations

Modification

Disease

Neuropathology

Behavior/Cognition

BACE1

BACE1: Transgenic

Alzheimer's Disease

Elevated extracellular multimeric Aβ, including Aβ*56 and Aβ hexamers, in the absence of plaques. At 12 months of age, astrogliosis was observed in a region- and genotype-dependent manner, especially in the dentate gyrus, hippocampal CA1, and piriform cortex. No overt tau pathology.

Largely intact motor coordination and gait (Rotarod, CatWalk). Age-associated changes in multiple measures of learning and memory. Early deficits in habituation to a novel environment and semantic-like memory (three-four months). Impaired spatial learning and long-term reference (Morris water maze) and working memory (Y-maze) at six months, distinct from reduced locomotor activity and anxiety.

Synaptic Loss at

Age-associated development of plaques: none at 3 months, overt Aβ deposition in the brain at approximately 6 months, with heavy plaque load in the hippocampus, frontal cortex, and subiculum at 10 months. Aβ deposits in blood vessels were sporadic, mainly in large vessels. Cerebral amyloid deposits correlate with levels of the human APP transcript at 12 months.

Cognitive impariment detected by the Morris water maze at 8 and 12 months of age, but not at 3 months.

Observed

X

Plaques at 39

Rare amyloid deposits at 5 months, with consistent deposits in the subiculum and frontolateral cortices by 9 months. Plaques increase in number and distribution over time, spreading throughout the neocortex and hippocampus as well as the amygdala and thalamic and pontine nuclei (Richards et al., 2003).

X

Gliosis at 39

An inflammatory response indicated by the presence of activated microglia and astrocytes begins around 9 months. The onset, distribution, and abundance of activated microglia and astrocytes correlate with Aβ deposition.

X

Cognitive Impairment at 35

Age-associated cognitive impairment from 8 months with impaired acquisition of spatial learning in the water maze (Richards et al., 2003).

Absent

Tangles at

Absent.

Changes in LTP/LTD at

No difference in LTP in the dentate gyrus at 3 and 10 months compared to wild-type mice (Richards et al., 2003).

No Data

Neuronal Loss at

Unknown.

Synaptic Loss at

Rare amyloid deposits at 5 months, with consistent deposits in the subiculum and frontolateral cortices by 9 months. Plaques increase in number and distribution with time, spreading throughout the neocortex and hippocampus as well as the amygdala and thalamic and pontine nuclei. The distribution and abundance of activated microglia and astrocytes correlate with Aβ deposition.

Mice develop age-associated cognitive impairment from 8 months with impaired acquisition of spatial learning in the water maze.

Observed

Absent

No Data

Observed

X

Neuronal Loss at 79

Neuronal loss in the CA1 region of the hippocampus has been reported at 22 months accompanied by reduced glucose utilization (Sadowski et al., 2004).

X

Plaques at 26

Large amounts of Aβ accumulate in the cerebral cortex and hippocampus, starting around 6 months and increasing with age. Other brain regions are affected later. Both diffuse and fibrillar plaques form (Gordon et al., 2002).

X

Gliosis at 26

GFAP-positive astrocytes appear first in the cortex in the vicinity of the developing Aβ deposits. Numbers increase with age, becoming confluent. Numbers of resting microglia (positive for complement receptor-3) increase in the vicinity of deposits at 6 months, but activated microglia (positive for MHC-II) are negligible before 12 months and more variable (Gordon et al., 2002).

X

Cognitive Impairment at 12

Double and single transgenic mice had reduced spontaneous alternation performance in a “Y” maze, a test of spatial memory, at 12-14 weeks, before substantial Aβ deposition (Holcomb et al., 1998). Progressive age-related cognitive impairment is seen later in select tasks (e.g. water maze acquisition and radial arm water maze working memory)(Arendash et al., 2001).

Absent

Tangles at

Neurofibrillary tangles are not associated with this model, but hyperphosphorylated tau is detected, starting at 24 weeks, appearing as punctate deposits near amyloid deposits in the cortex and hippocampus (Kurt et al., 2003).

No Data

Synaptic Loss at

Unknown.

Changes in LTP/LTD at

Aβ accumulates in the cerebral cortex and hippocampus starting ~6 months and increasing with age. Other regions affected later. Deposition occurs in white matter, cerebrovasculature, and grey matter in the form of diffuse and fibrillar plaques. Fibrillar deposits are associated with dystrophic neurites and GFAP-positive astrocytes at ~ 6 months with later microglial activation.

Progressive impairment between 5–7 and 15–17 months in some tests of cognitive performance, but not others. No change in anxiety levels.

Observed

X

Neuronal Loss at 9

Significant increase (about 8-fold) in apoptotic neurons at 2 months of age, although the total number of cortical neurons is not significantly altered due to the low basal level of apoptosis in the cerebral cortex. By 4 months of age, the cumulative loss of cortical neurons reaches about 9 percent of all cortical neurons.

X

Gliosis at 17

Astrogliosis and microgliosis; up-regulation of GFAP and other inflammatory markers are observed in the neocortex and hippocampus at 6 months, and this increases with age (Wines-Samuelson et al., 2010, Beglopoulos et al., 2004).

Synaptic Loss at 26

Cognitive Impairment at 9

Deficits in the Morris water maze and contextual fear conditioning are mild at 2 months, but become more severe with age (Saura et al., 2004).

Absent

Plaques at

Absent.

Tangles at

Tangles are absent, but hyperphosphorylation of tau has been reported in 9 month-old mice.

No Data

Genes

Mutations

Modification

Disease

Neuropathology

Behavior/Cognition

PSEN1, PSEN2

PSEN1: Conditional Knock-out; PSEN2: Knock-Out

Alzheimer's Disease

At 2 months the number of apoptotic neurons is elevated about 8-fold. By 6 months, about 18 percent of of cortical neurons are lost. Up-regulation of inflammatory markers and progressive astrogliosis and microgliosis in the neocortex and hippocampus.

Impairments in hippocampal learning and memory as indicated by Morris water maze and contextual fear conditioning evident by 2 months and worsens with age.

Observed

Absent

No Data

Observed

X

Neuronal Loss at 9

Expression of the tetracycline transactivator (tTA) resulted in reduced forebrain weight and smaller dentate gyri in rTg9191 mice compared to non-Tg littermates. This effect was also observed in mice expressing tTA alone, and is thought to be a developmental effect, as it was observed even in young mice (e.g., 2-6 months of age).

X

Plaques at 35

Plaques emerge first in the cerebral cortex, starting around 8 months of age. This is followed by plaques in the hippocampus at 10.5 to 12.5 months of age. Some dense core plaques develop.

X

Gliosis at 104

rTg9191 mice develop reactive gliosis (astrocytosis and microgliosis) in the vicinity of dense-core plaques by 24 months of age.

Absent

Tangles at

Tangles are not observed, but hyperphosphorylated tau develops with age.

Cognitive Impairment at

No transgene-related deficits seen in Morris water maze (4, 12, 21, 24 months of age) or fixed consecutive number test (23 months of age).

Observed

X

Neuronal Loss at 83

Neuronal loss is detectable by 24 months of age in areas with transgene expression (e.g. layer II of the EC and parasubiculum), compared with age-matched mice expressing only tTA. Significant neuronal loss was not observed at 21 months (de Calignon et al., 2012).

X

Tangles at 78

By 18 months of age, Gallyas silver-positive staining is observed, indicative of paired helical filaments. This is followed by thioflavin-S staining at 24 months. Tau pathology develops first in neurons of the medial EC expressing human tau, followed by neurons in the dentate gyrus, CA1 and CA2/3(de Calignon et al., 2012).

X

Gliosis at 104

Synaptic Loss at 104

By 24 months of age pre- and post-synaptic densities were reduced in the middle third of the molecular layer of the dentate gyrus as measured by synapsin-1 and PSD-95 staining (de Calignon et al., 2012).

X

Changes in LTP/LTD at 70

At 16 months of age, subtle differences in electrophysiological properties have been observed in the perforant pathway, including a decrease in LTP and an increase in the probability of neurotransmitter release (Polydoro et al., 2014).

X

Cognitive Impairment at 70

Very mild and specific deficits in contextual fear conditioning at 16 months of age, but no deficits in the radial arm maze (Polydoro et al., 2014).

Absent

Plaques at

Absent.

No Data

Propagating tau pathology starting in the entorhinal cortex and spreading to regions functionally connected to the EC (e.g., dentate gyrus). Neurodegeneration and axonal degeneration, first in EC and parasubiculum. Gliosis and synaptic loss.

Subtle cognitive deficit in contextual fear conditioning, but not in the radial arm maze, at 16 months. Mild specific deficit in locomotor activity in the open field test.

Synaptic Loss at 35

Cognitive Impairment at 11

No significant abnormalities at 1.3 months but retention of spatial memory (Morris Water Maze) became impaired from 2.5 to 4 months. No significant motor impairments up to 6 months. Spatial memory improved when transgene suppressed by dox.

Absent

Plaques at

Absent.

No Data

Changes in LTP/LTD at

Electrophysiological properties of cortical neurons are altered as early as 1 to 3 months of age. In freely behaving mice, individual neocortical pyramidal neurons are less active as is the neocortical network as a whole. Hyperexcitability of cortical neurons has been observed in vitro, along with effects on resting membrane potential and action potential firing rates.

Argyrophilic tangle-like inclusions in cortex by 4 months and in hippocampus by 5.5 months. Decreased CA1 neurons (~60 percent) by 5.5 months. Gross forebrain atrophy by 10 months. The number of CA1 neurons stabilized after a brief (six to eight week) suppression of transgenic tau.

No significant abnormalities at 1.3 months in the Morris Water Maze. Spatial memory impairments by 2.5 to 4 months. No significant motor impairment up to 6 months of age. When the transgene was suppressed with dox at 2.5 months, spatial memory improved.

Observed

Absent

No Data

Genes

Mutations

Modification

Disease

Neuropathology

Behavior/Cognition

Spontaneous

Alzheimer's Disease

Age-associated increase in hippocampal Aβ from 4 to 12 months, but no plaque-like structures by Congo red or thioflavine S. Spongiform degeneration: vacuoles of various size in the neuropil in the brain stem. Microglial cell proliferation. Degeneration of dopamine neurons in the substantia nigra and noradrenaline neurons in the locus coeruleus.

Observed

Plaques at 52

Fibrillar amyloid plaques develop by 12 months in the cortex and hippocampus.

X

Gliosis at 26

Astrogliosis and microgliosis underway by 6 months of age in the dentate gyrus.

X

Synaptic Loss at 104

TAS10 mice initially have more synapses than non-Tg mice; specifically, greater numbers of synapses per neuron were documented at 12 and 18 months of age. However, by 24 months of age, TAS10 mice have fewer synapses than non-Tg mice.

X

Cognitive Impairment at 26

Deficits in spatial learning present by 6 months of age as measured by the Morris water maze. No difference from non-Tg at 2 months of age. Deficits in Y maze at 12 months. No deficit in fear conditioning up to 24 months of age.

Absent

Neuronal Loss at

Qualitative difference in neuronal numbers at 24 months in specific regions of the hippocampus, but no significant neuronal loss.

Tangles at

Absent.

Changes in LTP/LTD at

At 12 to 14 months of age, deficits in basal synaptic transmission have been observed in the CA1 region, but short- and long-term synaptic plasticity are relatively normal (Brown et al., 2005).

No Data

Age-related accumulation of Aβ in the hippocampus and cortex leading to plaque deposition by 12 months of age. Early gliosis and dystrophic neurites, not limited to the vicinity around plaques. Changes in synaptic morphology and number, along with increased number of lysosomes.

Deficits in spatial memory prior to Aβ deposition, including deficits in the Morris water maze by 6 months Deficits in spontaneous alternation behavior in the Y maze by 12 months. No deficit in fear conditioning.

Observed

X

Plaques at 26

Aβ begins to deposit at 3 months of age, with fibrillar plaques evident by 6 months in the cerebral cortex and hippocampus. Some vascular amyloid is also observed. Plaque pathology is more severe in female mice.

X

Gliosis at 28

Greater numbers of reactive astrocytes and microglia by 6 months of age in the hippocampus and cortex, predominantly near amyloid plaques.

X

Cognitive Impairment at 26

Age-dependent impairment in object recognition memory starting around 6 months of age for both sexes. No impairment at 3 to 4 months of age.

Absent

Neuronal Loss at

Minimal neuronal loss up to 10 months of age. Some signs of loss in the immediate vicinity of plaques in the hippocampus (Howlett et al., 2008).

Tangles at

Absent.

No Data

Synaptic Loss at

Unknown.

Changes in LTP/LTD at

Aβ deposits beginning at 3 months of age, with fibrillar plaques by 6 months in the cerebral cortex and hippocampus. Some vascular amyloid. Plaques surrounded by dystrophic neurites and reactive glia. No tangles or neuronal loss. Female mice have more rapid and severe amyloid pathology.

Observed

X

Tangles at 35

Abnormally phosphorylated tau detected at two months and by eight months tau was mislocalized and misfolded and dystrophic neurites were observed. Tangle-like structures observed in the hippocampus by 14 months.

X

Synaptic Loss at 61

At 14 months synapsin1 protein levels were decreased but synaptophysin levels remained at wild-type levels.

X

Cognitive Impairment at 36

In the Morris water maze, Tau35 had the same performance as wild-type animals at six months but developed progressive deficits by eight months.

Absent

Gliosis at

Gliosis was not observed at 14 months.

No Data

Neuronal Loss at

Cell death was not formally assessed, however, overt neuronal death was not seen in the hippocampus.

Absent

Neuronal Loss at

Plaques at

Tangles at

No Data

Gliosis at

Synaptic Loss at

Unknown.

Changes in LTP/LTD at

Unknown.

Genes

Mutations

Modification

Disease

Neuropathology

Behavior/Cognition

MAPT

MAPT: Transgenic

Frontotemporal Dementia, Other Tauopathy, Alzheimer's Disease

Extensive pretangle pathology throughout the brain (e.g. phospho- tau) but no mature neurofibrillary tangles and only mild oligomeric tau, restricted to the CA1 region of the hippocampus. Dystrophic neurites and axonal pathology (spheroids). No overt neuronal loss.

Observed

X

Neuronal Loss at 65

Significant loss of NeuN-positive neurons in layer II of the entorhinal cortex at 15 months, and in the hippocampal CA1 region at 24 months, compared with non-Tg controls. No difference in the hippocampus at 18 months.

X

Tangles at 65

Gallyas silver-positive intracellular inclusions of hyperphosphorylated tau aggregates in the entorhinal cortex at 15 months, and in the hippocampus and cerebral cortex at 24 months, but not at 18 months.

X

Gliosis at 52

At 12 months of age, Iba1-positive cells are observed. GFAP is observed at 24 months of age.

X

Synaptic Loss at 28

Reduced synaptic density at 6 months of age in select hippocampal areas compared to non-Tg mice and those expressing wild-type human tau. Densities in other areas were comparable until later ages (i.e., 24 months).

X

Changes in LTP/LTD at 26

Some changes in basal synaptic transmission and significant impairment of LTP evident by 6 months of age in some regions of the hippocampus.

X

Cognitive Impairment at 26

Deficits in spatial reference memory by 6 months of age as measured by the Morris water maze. No difference from non-Tg littermates at 4 months of age.

Observed

X

Tangles at 104

Mature tangles are observed only at advanced age (>24 months), but extensive pre-tangle pathology develops with as little as three months of transgene expression. This includes mislocalization of tau to the somatodendritic compartment, conformational changes indicative of aggregation, and hyperphosphorylation (e.g. Ser 262, Ser 356).

X

Synaptic Loss at 57

Electron microscopy showed a moderate decrease in spine synapses in the CA1 region of the hippocampus following 13 months of gene expression.

X

Changes in LTP/LTD at 52

Impaired hippocampal LTP in the CA1 and CA3 areas.

X

Cognitive Impairment at 70

Cognitive deficits in the Morris water maze and in passive-avoidance paradigms.

Absent

Neuronal Loss at

Absent.

Plaques at

Absent.

No Data

Gliosis at

Abundant pre-tangle pathology, but only rare mature tangles, and only at advanced ages. Tau pathology included mislocalization of tau to the somatodendritic compartment, aggregation, and hyperphosphorylation.

Observed

Tangles at 35

Gliosis at 30

Changes in LTP/LTD at 26

Deficit in LTP in CA1 region of the hippocampus at 6 months, but enhanced LTP in the dentate gyrus at a young age (8-10 weeks).

X

Cognitive Impairment at 22

Age-associated deficit in two cognitive tests that do not depend heavily on motor ability, the passive avoidance task (significant deficit starting at 5 months, but not 2 or 3 months of age) and a novel object recognition task (significant deficit at 9 months, but not at 2, 3, 5, or 7 months of age) (Maurin et al., 2014).

Absent

Plaques at

Absent.

No Data

Neuronal Loss at

Unknown.

Synaptic Loss at

Unknown at advanced age.
Young mice (1-2 months) have a significantly higher spine maturation index than controls. At 4-6 months, the spine maturation index remains high in the hippocampus, but is reduced to control levels in the cortex. Note, these results were generated using the progeny of Tau P301L x transgenic Thy1-YFP (Kremer et al., 2011).

Pathologic hyperphosphorylation and conformational change of parenchymal tau in brain tissues starting at 7 months. Tangle-like pathology is mainly observed in the brain stem and spinal cord, and to a lesser extent in the midbrain and cerebral cortex. Age-dependent increase in total tau in CSF.

Age-associated deficits in a passive avoidance task (starting at 5 months) and a novel object recognition task (starting at 9 months). At a young age (~2 months) outperforms wild-type littermates in object recognition memory. Progressive motor impairment and reduced activity, accompanied by increased clasping of hind and then forelimbs around seven months.

Tangles at 23

Gliosis at 11

Microgliosis at three months, especially in the white matter of the brain and spinal cord. Increased microgliosis by six months in white and gray matter of the hippocampus, amygdala, entorhinal cortex, and spinal cord. Microglial activation precedes astrogliosis (Yoshiyama et al., 2007).

X

Synaptic Loss at 13

Synaptophysin immunoreactivity decreased progressively from three to six months in the CA3 region of the hippocamus. Impaired synaptic function (Yoshiyama et al., 2007).

Absent

Plaques at

No Data

Neuron loss and brain atrophy by eight to 12 months, especially in the hippocampus and spreading to the neocortex and entorhinal cortex. Neurofibrillary tangles in the neocortex, amygdala, hippocampus, brain stem, and spinal cord. Neuroinflammation with microgliosis and astrocytosis.

Impairments in spatial memory and learning ability in Morris water maze. Paralysis at seven to 10 months associated with a hunched-back posture followed by feeding difficulties. About 80 percent mortality by 12 months with median survival of about nine months.

Observed

X

Plaques at 17

Rare amyloid plaques at 4 months, plaques become more abundant with age. By 8 months the number of amyloid plaques increases considerably in the subiculum and the CA1 region of the hippocampus (Grueninger et al., 2010).

X

Tangles at 70

Abnormally phosphorylated tau is detectable at 4 months in both TauPS2APP and tau single transgenic mice especially in the subiculum, amygdala, and the CA1 region of the hippocampus. Tau pathology increases with age with numerous tangle-like deposits in the hippocampus confirmed by Gallyas silver staining at 16 months (Grueninger et al., 2010).

X

Cognitive Impairment at 17

Impairment is not age-associated and does not progress from age 4 months to 12 months (Grueninger et al., 2010).

Phosphorylated tau accumulation in the subiculum and the CA1 region of the hippocampus at 4 months. Neurofibrillary tangles in these regions as well as the amygdala. Amyloid plaques. Dystrophic neurites and neuropil threads containing abnormally phosphorylated tau. No overt neuronal loss.

Impaired spatial learning in the Morris water maze at 4 months but impairment is not progressive between 4 and 12 months and appears to be independent of pathology.

Gliosis at

Synaptic Loss at

Changes in LTP/LTD at

Argyrophilic and congophilic tau inclusions in neurons of the forebrain with age. Detectable with Congo red, thioflavin-S and Gallyas silver stain. Congophilic tau inclusions also in the hippocampus and amygdala. Mainly straight tau filaments.

Observed

X

Neuronal Loss at 22

Neuronal loss in the dentate gyrus (granule neurons) following 5 months of transgene expression. Shrinkage of the molecular layer of the hippocampus.

X

Tangles at 9

Tau tangles and aggregates with as little as 2-3 months of transgene expression. Tangles start in the entorhinal cortex and amygdala and spread to the neocortex by 15 months. Heterogeneous tangle morphology, including flame-shaped.

X

Gliosis at 91

Astrogliosis in the hilus region of the hippocampus after 21 months of transgene expression. Additional increases in GFAP-positive astrocytes in the entorhinal and piriform cortices.

X

Synaptic Loss at 41

Hippocampal synaptic loss as indicated by multiple measures following 9.5 months of transgene expression. Reduced synaptophysin immunoreactivity and reduced number of spine synapses as measured by electron microscopy.

X

Changes in LTP/LTD at 43

Multiple deficits in synaptic plasticity, including deficits in LTP and LTD, after 10 months of transgene expression. Functional changes are associated with structural synaptic changes, local calcium dysregulation, and a decrease in the synaptic vesicle pool.

X

Cognitive Impairment at 43

Learning and memory impairments are apparent after 10 months of transgene expression as assessed by the Morris water maze and passive avoidance tasks.

Observed

X

Neuronal Loss at 43

Evidence of hippocampal neuronal degeneration in 10 month old animals: irregularly shaped neurons with tau pathology that stained with propidium iodide. As characteristics of apoptosis were not observed, the neurons were thought to be undergoing non-apoptotic atrophic degeneration (Tanemura et al., 2002).

X

Tangles at 48

Fibrillar staining in the hippocampus of 11 month old animals by Congo red birefringence. Absent in 4 month old mice, indicating the formation of these neurofilament-like structures occurs between 4 and 11 months (Tanemura et al., 2001).

X

Changes in LTP/LTD at 65

In hippocampal slices there was an attenuation of the amplitude of Schaffer collateral evoked hippocampal depolarization (Tanemura et al., 2002).

X

Cognitive Impairment at 48

Behavioral abnormalities measured in 11 month-old mice. They spent more time in the open arms of the elevated plus maze and had greater overall locomoter activity. No differences in the Morris water maze compared with non-transgenic mice, suggesting the transgenic animals retain spatial recognition abilities (Tanemura et al., 2002).

Observed

Neuronal Loss at 52

Age-dependent neuronal loss in the CA1 region of the hippocampus. No difference from wild-type mice at 3 and 6 months of age, but approximately 35% loss at 12 months of age.

X

Plaques at 52

Very rare extracellular Aβ deposits.

X

Gliosis at 52

Marked gliosis in the hippocampus as measured by GFAP staining at 12 months.

X

Cognitive Impairment at 54

Age-dependent deficits in working and spatial reference memory at 12 months, but not at 3 and 6 months.

Absent

Tangles at

Absent.

No Data

Synaptic Loss at

Unknown.

Changes in LTP/LTD at

Unknown.

Genes

Mutations

Modification

Disease

Neuropathology

Behavior/Cognition

APP

APP: Transgenic

Alzheimer's Disease

Intraneuronal accumulation of Aβ peptides in the hippocampus by 3 months and in cerebellar nuclei by 6 months. Marked gliosis in the hippocampus by 12 months. Very rare extracellular Aβ deposits.

Age-dependent behavioral deficits, including working memory as assessed by the cross maze at 12 months, but not at 3 or 6 months. Early and persistent decrease in anxiety in the elevated plus maze. Comparable to wild-type in general motor coordination at 3 and 6 months as indicated by the balance-beam test, but impairment at 12 months.

Observed

X

Plaques at 48

Numerous parenchymal Aβ plaques by 11-13 months.

X

Gliosis at 43

Increase in microglial density and size in plaque-forming areas of the brain including the hippocampus, frontal cortex, entorhinal cortex, and occipital cortex in 10-16 month old hemizygotes (Frautschy et al., 1998).

X

Synaptic Loss at 20

Changes in LTP/LTD at 22

By 5 months, there was a decline in LTP in the dentate gyrus after perforant path stimulation compared to wild-type; impairment was not observed at 2 months (Jacobsen et al., 2006). Both the CA1 and dentate gyrus of aged mice (>15 months) are impaired (Chapman et al., 1999). Differences have been observed between the Schaffer collateral and mossy fiber pathways (Jung et al., 2011).

X

Cognitive Impairment at 26

Impaired spatial learning, working memory, and contextual fear conditioning at <6 months although other studies have reported normal cognition at this age with progressive impairment by >12 months.

Impaired spatial learning, working memory, and contextual fear conditioning reported at <6 months although other studies have reported normal cognition at this age with progressive impairment by >12 months.

Observed

X

Plaques at 39

Plaques develop gradually with age. No plaques at 5 months. Very few small plaques at 6 and 7 months. By 9 months plaques scattered throughout the cortex, hippocampus and amygdala, continue to increase at 12 months. Similar distribution as Tg2576.

X

Tangles at 13

Neurofibrillary tangles in the spinal cord and pons as early as 3 months, but more consistent and numerous by 6 months. Tangles morphologically similar to those in JNPL3 mice but older bigenic female mice had a marked increase in neurofibrillary tangles in limbic areas by 6 months, especially the olfactory cortex, entorhinal cortex and amygdala (Lewis et al., 2001).

X

Gliosis at 13

Reactive astrocytes and microglia as early as 3 months in the hippocampus as measured by GFAP and CD45. Increased astrocytosis with age especially in limbic areas with the most neurofibrillary tangles. Microglia especially concentrated around plaques at 9 and 12 months (Lewis et al., 2001).

Absent

No Data

Synaptic Loss at

Gradual appearance of plaques; by 9 months plaques are scattered throughout the cortex, hippocampus, and amygdala similar to Tg2576. Tau pathology more extensive than JNPL3. Astrocytosis and microgliosis.

Motor disturbances similar to JNPL3, with identical range in age of onset. Reduced vocalization and decreased grooming.

Observed

Neuronal Loss at 35

Age- and dose-dependent neuronal loss in the hippocampus CA1 region of hemizygous and homozygous mice. Compared with wild-type, hemizygous mice had 38% neuronal loss at 8 months, and 49% loss at 12 months. No difference at 3 months.

X

Gliosis at 9

Reactive microglia and astrocytes in the hippocampus starting at 2 months.

X

Synaptic Loss at 37

Altered synaptophysin staining in the CA3 region of the hippocampus. More pronounced in homozygous mice than hemizygous mice at 8 months.

X

Cognitive Impairment at 35

Spatial reference memory is impaired as assessed by Morris water maze at 8 months in homozygous mice and 12 months in hemizygous mice. Deficit is age-dependent and is not detected at 3 months. Impaired contextual fear conditioning at 12 months.

Absent

Plaques at

Absent.

Tangles at

Absent.

No Data

Changes in LTP/LTD at

Unknown.

Genes

Mutations

Modification

Disease

Neuropathology

Behavior/Cognition

APP

APP: Transgenic

Alzheimer's Disease

Aβ4-42 is dectable starting at two months, predominantly in the CA1 region of the hippocampus, but also in the occipital cortex, piriform cortex, striatum, and superior colliculus. Age- and dose-dependent hippocampal neuronal loss is seen in the CA1 region as well as microgliosis and astrogliosis.

Age-dependent spatial learning deficit as demonstrated in the Morris water maze, specifically, the absence of a preference for the target quadrant starting at eight months in homozygous mice and at 12 months in hemizygous mice. Impaired contextual fear conditioning.

Observed

Absent

No Data

Mild amyloid pathology with a relatively late onset, starting with intracellular Aβ, then diffuse extracellular Aβ deposits in the subiculum, expanding to interconnected brain regions such as retrosplenial granular cortex, thalamus, and mammillary bodies. Pathology more severe in females.

Observed

Absent

No Data

Observed

X

Plaques at 22

Extracellular amyloid plaque deposition starts at around 5-6 months of age (Lord et al., 2006) and is most consistently present in the cerebral cortex, hippocampus, and thalamus (Lillehaug et al., 2013).

X

Gliosis at 26

Microgliosis and astrogliosis most prominent in the hippocampus, but also locally around deposits in the cerebral cortex and thalamus.

Changes in LTP/LTD at

Strong intraneuronal Aβ aggregation starting at 1 month and increasing with age. Extracellular amyloid plaque at 5-6 months, most consistent in the cerebral cortex, hippocampus, and thalamus. Congophilic parenchymal plaques are predominant, but some mice show marked CAA, particularly in the thalamus.

Mild spatial learning deficits at 4-8 months in Morris water maze and impaired functioning in a passive avoidance test at 16 months.

Early impairment in acquisition and learning reversal in the reference memory version of the Morris water maze by 3 months. Cognitive deficits in the step-down inhibitory avoidance test at 7 months but not at 2 months. Similar to wild-type in motility, exploratory activity, or neuromuscular function at 7 months as evaluated by the rotarod, hole board and grip strength tests.

Widespread cerebral amyloid angiopathy (CAA) starting around 7 months. Deposition of the Danish amyloid subunit (ADan) in brain parenchyma and vessels, along with amyloid-associated gliosis and inflammation, intracellular and extracellular deposition of oligomeric ADan, and tau-positive deposits in neuropil, but no neurofibrillary tangles.

Age-dependent abnormal grooming behavior. Around one year mice develop an arched back and walk with a wide-based gait and short steps. Feet clasping upon suspension of the mice by their tails.

Observed

X

Plaques at 13

Hemizygotes progressively accumulate insoluble Aβ40 and Aβ42, especially within brain microvessels starting at 3 months. Amyloid-β deposits in the subiculum, hippocampus, and cortex at ~3 months. By ~6 months deposits become more numerous and appear in the olfactory bulb and thalamic region as well, with deposits throughout most of the forebrain by 12 months (Davis et al., 2004).

X

Gliosis at 26

Pronounced increase in the number of GFAP-positive astrocytes and activated microglia with age (6-24 months) especially in the thalamus and subiculum and to a lesser extent in the cortex (Miao et al., 2005).

X

Cognitive Impairment at 13

Impaired learning and memory in the Barnes maze task at 3, 9, and 12 months; beginning at 3 months took longer to find the escape hole. No difference in mobility, strength or coordination (Xu et al., 2007).

Impaired learning and memory in the Barnes maze task at 3, 9, and 12 months. Beginning at 3 months transgenic mice took longer to find the escape hole. No difference in mobility, strength or coordination.

Observed

X

Plaques at 52

Plaques are detectable at approximately 12 months and are heterogeneous in morphological structure and size, as well as in terms of fluorescence emitted when stained with luminescent polymers (conformational amyloid ligands)(Philipsson et al., 2009).

X

Gliosis at 52

Microgliosis and astrogliosis are most prominent in the hippocampus, but also found locally around deposits in the cerebral cortex and in thalamus at approximately 12 months (Philipsson et al., 2009).

Observed

X

Neuronal Loss at 52

Loss of cells in the CA1 region of the hippocampus from 12 months as measured by DAPI staining and Nissl/cresyl-violet (Schindowski et al., 2006). Also, a significant reduction in the number of choline acetyltransferase (ChAT)-immunopositive cholinergic neurons in the medial septum has been reported (Belarbi et al., 2011).

Observed

Absent

No Data

Brain is grossly normal. Age-dependent cholinergic neurodegeneration and reduced NGF in the basal forebrain. Age-related elevation of APP and Aβ in the hippocampus but no β-amyloid pathology.

Early developmental delay. Deficits in behavioral and cognitive tasks including spatial learning and memory deficits as assessed by the Morris water maze and the radial arm maze. Developmental delay in sensorimotor milestones. Locomotor hyperactivity. Lack of behavioral inhibition. Stereotypic behavior.